Aaltodoc Repository :: Browsing by Author "Koskinen, Ari M.P."

Browsing by Author "Koskinen, Ari M.P."

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The 9-Phenyl-9-fluorenyl Group for Nitrogen Protection in Enantiospecific Synthesis
(2010) Karppanen, Essi J.; Koskinen, Ari M.P.; Department of Chemistry
One of the biggest challenges in asymmetric synthesis is to prevent racemization of enantiopure starting materials. However, at least some of the enantiopurity is lost in most of the existing reactions used in synthetic organic chemistry. This translates into unnecessary material losses. Naturally enantiopure proteinogenic amino acids that can be transformed into many useful intermediates in drug syntheses, for example, are especially vulnerable to this. The phenylfluoren-9-yl (Pf) group, a relatively rarely used protecting group, has proven to be able to prevent racemization in α-amino compounds. This review article showcases the use of Pf-protected amino acid derivatives in enantiospecific synthesis.
a-methylated derivatives of 2-arachidonyl glycerol: Synthesis, CB1 receptor activity and enzymatic stability
(2006) Parkkari, Teija; Koskinen, Ari M.P.; Myllymäki, Mikko; Savinainen, Juha R.; Saario, Susanna M.; Castillo-Melendez, Joel A.; Laitinen, Jarmo T.; Nevalainen, Tapio; Järvinen, Tomi; Department of Chemistry
a-Methylated analogues of the endogenous cannabinoid, 2-arachidonoyl glycerol (2-AG), were synthesized aiming to the improved enzymatic stability of 2-AG. In addition, the CB1 activity properties of fluoro derivatives of 2-AG were studied. The CB1 receptor activity was determined by the [35S]GTPcS binding assay, and the enzymatic stability of a-methylated analogues was determined in rat cerebellar membranes. The results indicate that even if the a-methylated 2-AG derivatives are slightly weaker CB1 receptor agonists than 2-AG, they are clearly more stable than 2-AG. In addition, the results showed that the replacement of the hydroxyl group(s) of 2-AG by fluorine does not improve the CB1 activity of 2-AG.
Asymmetric organocatalytic Michael addition of Meldrum's acid to nitroalkenes: probing the mechanism of bifunctional thiourea organocatalysts
(2010) Kataja, Antti O.; Koskinen, Ari M.P.; Department of Chemistry
The asymmetric Michael addition of Meldrum’s acid to nitroalkenes was studied using a novel type of Cinchona alkaloid-based bifunctional thiourea organocatalyst. The functionality of the thiourea catalysts was also probed by preparing and testing thiourea-N-methylated analogues of the well-known bis-(3,5-trifluoromethyl)phenyl-substituted catalyst.
Asymmetric synthesis of Pachastrissamine (Jaspine B) and its diastereomers via ?3-allylpalladium intermediates
(2011) Passiniemi, Mikko; Koskinen, Ari M.P.; Department of Chemistry
A short route for the synthesis of Pachastrissamine (Jaspine B), an anhydrosphingosine derivative, and all three of its diastereomers is presented. The route consists of only 9 steps from the commercially available Garner’s aldehyde. The furan framework is formed via an h3-allylpalladium intermediate.
Biology and Chemistry of Sphingosine-Related Metabolies
(2004) Koskinen, Ari M.P.; Brunner, Martin; Department of Chemistry
Calyculins and Related Marine Natural Products as Serine-Threonine Protein Phosphatase PP1 and PP2A Inhibitors and Total Syntheses of Calyculin A, B, and C
(2010) Fagerholm, Annika E.; Habrant, Damien; Koskinen, Ari M.P.; Department of Chemistry
Calyculins, highly cytotoxic polyketides, originally isolated from the marine sponge Discodermia calyx by Fusetani and co-workers, belong to the lithistid sponges group. These molecules have become interesting targets for cell biologists and synthetic organic chemists. The serine/threonine protein phosphatases play an essential role in the cellular signalling, metabolism, and cell cycle control. Calyculins express potent protein phosphatase 1 and 2A inhibitory activity, and have therefore become valuable tools for cellular biologists studying intracellular processes and their control by reversible phosphorylation. Calyculins might also play an important role in the development of several diseases such as cancer, neurodegenerative diseases, and type 2-diabetes mellitus. The fascinating structures of calyculins have inspired various groups of synthetic organic chemists to develop total syntheses of the most abundant calyculins A and C. However, with fifteen chiral centres, a cyano-capped tetraene unit, a phosphate-bearing spiroketal, an anti, anti, anti dipropionate segment, an α-chiral oxazole, and a trihydroxylated γ-amino acid, calyculins reach versatility that only few natural products can surpass, and truly challenge modern chemists’ asymmetric synthesis skills.
Catalytic Activity Dependency on Catalyst Components in Aerobic Copper-TEMPO Oxidation
(2009) Kumpulainen, Esa T.T.; Koskinen, Ari M.P.; Department of Chemistry
The influence of catalyst components in the copper–TEMPO (2,2,6,6-tetramethylpiperidine N-oxide) catalysed aerobic oxidation of alcohols was investigated. The type and amount of base greatly influences reactivity. The bipyridyl ligand concentration had no major influence on catalysis, but excessive amounts led to a decrease in activity for longer reaction times. The kinetic dependency for TEMPO was found to be 1.15, and for copper 2.25, which is an indication of a binuclear catalytic system. Optimised conditions with various allylic and aliphatic alcohols give good to excellent rapid oxidations.
Chiral 3-(4,5-dihydrooxazol-2-yl)phenyl alkylcarbamates as novel FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and interaction fields
(2009) Myllymaki, Mikko J.; Kasnanen, Heikki; Kataja, Antti O.; Lahtela-Kakkonen, Maija; Saario, Susanna M.; Poso, Antti; Koskinen, Ari M.P.; Department of Chemistry
Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) are the main enzymes responsible for the hydrolysis of endogenous cannabinoids N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively. Phenyl alkylcarbamates are FAAH inhibitors with anxiolytic and analgesic activities in vivo. Herein we present for the first time the synthesis and biological evaluation of a series of chiral 3-(2-oxazoline)-phenyl N-alkylcarbamates as FAAH inhibitors. Furthermore, the structural background of chirality on the FAAH inhibition is explored by analyzing the protein–ligand interactions. Remarkably, 10-fold difference in potency was observed for (R)- and (S)-derivatives of 3-(5-methyl-4,5-dihydrooxazol-2-yl)phenyl cyclohexylcarbamate (6a vs. 6b). Molecular modelling indicated an important interaction between the oxazoline nitrogen and FAAH active site.
Chirospecific synthesis: Catalysis and chiral pool hand in hand
(2011) Koskinen, Ari M.P.; Department of Chemistry
Nature provides us with a wonderful pool of enantiopure starting materials for synthesis: amino acids, sugars, and many (but not all!) terpenes can be isolated even in large quantities in an uncompromised 100 % ee. Vicinal amino alcohols constitute a versatile group of organic structures; they are, in principle, available in enantiopure form from the chiral pool compounds or through chiral catalysis; they are potent intermediates for the synthesis of natural products and medicinally/biologically active compounds, and they provide a highly desirable scaffold for the construction of ligands for metals as well as organocatalysts. These new techniques will open up valuable new possibilities for the invention of new technologies for chemical synthesis, the desired course of chemical discoveries for the future. A robust entry to enantiopure vicinal amino alcohols from inexpensive naturally occurring amino acids has therefore become a key challenge for our endeavors in the development of methodology.
Cleavage of recombinant proteins at poly-His sequences by Co(II) and Cu(II)
(2007-08) Anberg, Martina; Jäntti, Jussi; Heilimo, Saara; Pihkala, Päivi; Paananen, Arja; Koskinen, Ari M.P.; Söderlund, Hans; Linder, Markus; Department of Chemistry; VTT Technical Research Centre of Finland
Improved ways to cleave peptide chains at engineered sites easily and specifically would form useful tools for biochemical research. Uses of such methods include the activation or inactivation of enzymes or the removal of tags for enhancement of recombinant protein expression or tags used for purification of recombinant proteins. In this work we show by gel electrophoresis and mass spectroscopy that salts of Co(II) and Cu(II) can be used to cleave fusion proteins specifically at sites where sequences of His residues have been introduced by protein engineering. The His residues could be either consecutive or spaced with other amino acids in between. The cleavage reaction required the presence of low concentrations of ascorbate and in the case of Cu(II) also hydrogen peroxide. The amount of metal ions required for cleavage was very low; in the case of Cu(II) only one to two molar equivalents of Cu(II) to protein was required. In the case of Co(II), 10 molar equivalents gave optimal cleavage. The reaction occurred within minutes, at a wide pH range, and efficiently at temperatures ranging from 0°C to 70°C. The work described here can also have implications for understanding protein stability in vitro and in vivo.
Computer-assisted discovery of novel amino acid derived sulfides for enantioselective epoxidation of aldehydes
(2001) Myllymäki, Vesa T.; Lindvall, Mika K.; Koskinen, Ari M.P.; Department of Chemistry
Concise, stereodivergent and highly stereoselective synthesis of cis- and trans-2-substituted 3-hydroxy-piperidines - development of a phosphite-driven cyclodehydration
(2014) Huy, Peter H.; Westphal, Julia C.; Koskinen, Ari M.P.; Department of Chemistry
A concise (5 to 6 steps), stereodivergent, highly diastereoselective (dr up to >19:1 for both stereoisomers) and scalable synthesis (up to 14 g) of cis- and trans-2-substituted 3-piperidinols, a core motif in numerous bioactive compounds, is presented. This sequence allowed an efficient synthesis of the NK-1 inhibitor L-733,060 in 8 steps. Additionally, a cyclodehydration-realizing simple triethylphosphite as a substitute for triphenylphosphine is developed. Here the stoichiometric oxidized P(V)-byproduct (triethylphosphate) is easily removed during the work up through saponification overcoming separation difficulties usually associated to triphenylphosphine oxide.
Conformational control in stereoselective chemical reactions: From amino acids to iminosugars
(Japan Institute of Heterocyclic Chemistry, 2021) Koskinen, Ari M.P.; Department of Chemistry and Materials Science; Organic Chemistry
Two alternative synthetic strategies for the synthesis of vicinal amino alcohols from naturally occurring amino acids have been investigated, viz. one going through diastereoselective addition of organometallic species to an amino aldehyde and one going through α'-chiral α,β-enones and their diastereoselective reduction. Based on these investigations we were able to develop a synthetic strategy towards all diastereomers of deoxynojirimycin starting from naturally occurring serine through a divergent route with a late stage intermediate that can be prepared in large quantities and in enantiomerically pure form.
Conformational ensembles of flexible beta-turn mimetics in DMSO-d(6)
(2010) Koivisto, Jari J.; Kumpulainen, Esa T.T.; Koskinen, Ari M.P.; Department of Chemistry
b-Turns play an important role in peptide and protein chemistry, biophysics, and bioinformatics. The aim of this research was to study short linear peptides that have a high propensity to form b-turn structures in solution. In particular, we examined conformational ensembles of b-turn forming peptides with a general sequence CBz-L-Ala-L-Xaa-Gly-L-Ala-OtBu. These tetrapeptides, APGA, A(4R)MePGA, and A(4S)MePGA, incorporate proline, (4R)-methylproline, and (4S)-methylproline, respectively, at the Xaa position. To determine the influence of the 4-methyl substituted prolines on the b-turn populations, the NAMFIS (NMR analysis of molecular flexibility in solution) deconvolution analysis for these three peptides were performed in DMSO-d6 solution. The NBO (natural bond orbital) method was employed to gain further insight into the results obtained from the NAMFIS analysis. The emphasis in the NBO analysis was to characterize remote intramolecular interactions that could influence the backbone-backbone interactions contributing to b-turn stability. NAMFIS results indicate that the enantiospecific incorporation of the methyl substituent at the Cg (C4) position of the proline residue can be used to selectively control the pyrrolidine ring puckering propensities and, consequently, the preferred f,y angles associated with the proline residue in b-turn forming peptides. The NAMFIS analyses show that the presence of (4S)-methylproline in A(4S)MePGA considerably increased the type II b-turn population with respect to APGA and A(4R)MePGA. The NBO calculations suggest that this observation can be rationalized based on an n→p* interaction between the N-terminus alanine carbonyl oxygen and the proline carbonyl group. Several other interactions between remote orbitals in these peptides provide a more detailed explanation for the observed population distributions.
Conversion of carbonyl compounds to alkynes: general overview and recent developments
(2010) Habrant, Damien; Rauhala, Vesa; Koskinen, Ari M.P.; Department of Chemistry
The preparation of alkynes from carbonyl compounds via a one-carbon homologation has become a very useful pathway for the synthesis of acetylenic compounds, both internal and terminal. This tutorial review provides an overview of the different methods available for this transformation, including their scope and limitations, recent developments and applications in total syntheses.
Copper Catalyzed Alcohol Oxidation and Cleavage of β-O-4 Lignin Model Systems: From Development to Mechanistic Examination
(WILEY-V C H VERLAG GMBH, 2018-11-30) Salonen, H. Eemil P.; Mecke, Carsten P.A.; Karjomaa, Miika I.; Joensuu, Pekka M.; Koskinen, Ari M.P.; Department of Chemistry and Materials Science; Organic Chemistry; Aalto University
Lignin, an abundant natural polymer with high aromaticity, is a potential source of renewable chemicals and fuels among other biomaterials. Herein, a study on copper catalyzed alcohol oxidation and cleavage of lignin β-O-4 model substrates is reported. The potential of CuX/BiPy/TEMPO(/additive) systems (X=halide or triflate, BiPy=2,2’-bipyridine; TEMPO=2,2,6,6-tetramethylpiperidine-N-oxyl) was explored and the optimized protocol was studied with several type of model compounds. Mechanistic studies elucidated two types of cascade reactions: Both involve a cleavage of Cα–Cβ bond, which is most likely activated by 1) primary alcohol oxidation in β-O-4 glycerolaryl ethers resulting in retro-aldol cleavage and 2) Cβ–H oxidation after secondary alcohol oxidation in β-O-4 ethanolaryl ethers leading to oxidative radical cleavage. The first process affords aromatic aldehydes while the latter delivers aryl acids.
Design, Synthesis, and In Vitro Evaluation of Carbamate Derivatives of 2-Benzoxazolyl- and 2-Benzothiazolyl-(3-hydroxyphenyl)-methanones as Novel Fatty Acid Amide Hydrolase Inhibitors
(2007) Myllymäki, Mikko J.; Saario, Susanna M.; Kataja, Antti O.; Castillo-Melendez, Joel A.; Nevalainen, Tapio; Juvonen, Risto O.; Järvinen, Tomi; Koskinen, Ari M.P.; Department of Chemistry
Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase, which catalyzes the hydrolysis of the endocannabinoid N-arachidonoylethanolamide to arachidonic acid and ethanolamine. FAAH also hydrolyzes another endocannabinoid, 2-arachidonoylglycerol (2-AG). However, 2-AG has been assumed to be hydrolyzed mainly by monoacylglycerol lipase (MAGL) or a MAGL-like enzyme. Inhibition of FAAH or MAGL activity might lead to beneficial effects in many physiological disorders such as pain, inflammation, and anxiety due to increased endocannabinoid-induced activation of cannabinoid receptors CB1 and CB2. In the present study, a total of 34 novel compounds were designed, synthesized, characterized, and tested against FAAH and MAGL-like enzyme activity. Altogether, 16 compounds were found to inhibit FAAH with half-maximal inhibition concentrations (IC50) between 28 and 380 nM. All the active compounds belong to the structural family of carbamates. Compounds 14 and 18 were found to be the most potent FAAH inhibitors, which may serve as lead structures for novel FAAH inhibitors.
Diastereoselective Intramolecular Allyl Transfer from Allyl Carbamate Accompanied by 5-endo-trig Ring Closure
(2013) Karjalainen, Oskari K.; Nieger, Martin; Koskinen, Ari M.P.; Department of Chemistry
Diastereoselective Synthesis of Substituted Chromenopyrrolidinones from Amino Acid-Derived Nitriles
(Georg Thieme Verlag, 2023-01-03) Heikinheimo, Annakaisa; Nieger, Martin; Koskinen, Ari M.P.; Department of Chemistry and Materials Science; Organic Chemistry; University of Helsinki
Novel, substituted chromenopyrrolidininones have been synthesized from natural amino acid derivatives through an unprecedented sequence involving a Knoevenagel-Transesterification sequence and an allylative palladium-catalyzed cyclization reaction. The products are nature-inspired heterocycles derived from natural amino acids. The targets could be synthesized with varying degrees of stereoselectivity: racemization is a known issue with amino acids and provided a formidable challenge to our method development, as well. Altogether, six derivatives were synthesized with yields from moderate to good.
Enantioselective synthesis of a hindered furyl substituted allyl alcohol intermediate: a case study in asymmetric synthesis
(2004) Pihko, Ainoliisa J.; Lundell, Katri; Kanerva, Liisa; Koskinen, Ari M.P.; Department of Chemistry
In the course of the synthesis of the DEFG ring system of cneorin C 1, we were faced with the task of preparing the furyl substituted allyl alcohol 5 enantioselectively. Several different methods starting from enantioselective zinc-mediated alkylations were attempted, but none of them proved entirely satisfactory. The solution turned out to be enzymatic kinetic resolution through a highly enantioselective (E > 300) acylation in the presence of Candida antarctica lipase A.

Browsing by Author "Koskinen, Ari M.P."

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